e13512 Background: Lung cancer with family history have been emerging gradually of late years in East Asian, especially those presenting as pulmonary ground-glass nodules (GGNs). The predisposition of GGNs with lung cancer family history remains baffling. Methods: This prospective study was registered at clinicaltrials.gov (number NCT04220268) and enrolled patients with pulmonary pre-invasive or invasive adenocarcinoma, especially presenting as GGNs. We collected blood and tumor samples from 29 GGNs patients with family history to investigated germline and somatic mutations by whole exome sequencing (WES). As the first part of our study, we focused on 107 nonoverlapping susceptibility loci for lung carcinogenesis identified by recent genome-wide association studies (GWAS) to identify novel rare causal variants. Potential causal variants were further verified in other patients from the families when possible. Results: A total of 461267 single neocleotide variants (SNVs) and 132268 insertion-deletions (InDels) were detected from the 29 index patients. By focusing on exome profiles of the 107 target loci, we identified three key rare mutations, namely MSH5 p.Ala702Thr, ADGRG6 p.Asn338Ile and CCDC147 p.Arg619Trp in two index patients respectively. The minor allele frequency (MAF) of these three variants was extremely low in the general population, which is 1/5008, 2/5008 and 6/5008 respectively in the 1000 Genomes database, and 2/31406, 5/31346, and 5/31394 respectively in the GnomAD database. There three mutations were predicted as probably damaging or disease-causing variations by SIFT or Polyphen. Mutations of MSH5 and CCDC147 were also detected in other patients from the two families. Conclusions: With the identification of highly disruptive risk-conferring MSH5, ADGRG6 and CCDC147 mutations, we confirmed the probably heritable and risk loci exists in the GGNs patients with lung cancer family history in East Asians. Exome sequencing has great potential to identify novel rare causal variants, and more analyses on more patients are still ongoing.